Laboratories of Molecular and Cell Biology, University Hospital Bulovka and 3rd Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
Int J Oncol. 2012 Jun;40(6):2111-21. doi: 10.3892/ijo.2012.1397. Epub 2012 Mar 7.
The Apaf-1 interacting protein (APIP) and the uveal autoantigen with coiled coil domains and ankyrin repeats (UACA) belong to endogenous regulators of the apoptosome apparatus, but their role in tumourigenesis and progression of non-small cell lung carcinoma (NSCLC) is not known. Previous studies demonstrated that APIP inhibits the apoptosome-mediated procaspase-9 activation while UACA induces translocation of Apaf-1 from the cytoplasm into the nucleus. Here, we report for the first time that the expression of APIP and UACA genes is down-regulated on the level of both mRNA and protein in NSCLC cells and tumours. In particular, the expression of APIP protein was strikingly decreased and the expression of UACA mRNA and protein was frequently down-regulated in NSCLC tumours of different histopathological types. Moreover, stage IA NSCLC tumours showed significantly lower expression of UACA mRNA compared to higher stage tumours. The weak increase of both APIP and UACA mRNA levels in the 5-aza-2'-deoxycytidine-treated NSCLC cells indicates that mechanisms other than DNA methylation are involved in the regulation of APIP and UACA gene expression in these cancer cells. Taken together, the down-regulation of APIP and UACA expression suggests that the threshold to activate the apoptosome apparatus may be decreased in NSCLC cells due to the lack of APIP-mediated suppression and UACA-assisted Apaf-1 nuclear entry. Moreover, the loss of UACA-assisted Apaf-1 nuclear translocation may underlie the failure of DNA damage checkpoint activation in NSCLC cells leading to their genomic instability.
凋亡蛋白酶激活因子-1 相互作用蛋白 (APIP) 和带有卷曲螺旋结构域和锚蛋白重复序列的葡萄膜自身抗原 (UACA) 属于凋亡体装置的内源性调节剂，但它们在非小细胞肺癌 (NSCLC) 的肿瘤发生和进展中的作用尚不清楚。先前的研究表明，APIP 抑制凋亡体介导的 procaspase-9 激活，而 UACA 诱导 Apaf-1 从细胞质易位到细胞核。在这里，我们首次报道 APIP 和 UACA 基因的表达在 NSCLC 细胞和肿瘤中均在 mRNA 和蛋白质水平下调。特别是，APIP 蛋白的表达明显降低，不同组织病理学类型的 NSCLC 肿瘤中 UACA mRNA 和蛋白的表达经常下调。此外，IA 期 NSCLC 肿瘤的 UACA mRNA 表达明显低于较高分期的肿瘤。5-aza-2'-脱氧胞苷处理的 NSCLC 细胞中两者的 APIP 和 UACA mRNA 水平的微弱增加表明，除了 DNA 甲基化之外，其他机制参与了这些癌细胞中 APIP 和 UACA 基因表达的调控。总之，APIP 和 UACA 表达的下调表明，由于缺乏 APIP 介导的抑制和 UACA 辅助的 Apaf-1 核内进入，NSCLC 细胞中激活凋亡体装置的阈值可能降低。此外，UACA 辅助的 Apaf-1 核易位的丧失可能是 NSCLC 细胞中 DNA 损伤检查点激活失败的基础，导致其基因组不稳定。
